Hydroxamic acid esters

ABSTRACT

O-substituted hydroxylamines of the formula I 
     
         H.sub.2 NOR.sub.1                                          (I) 
    
     in which 
     R 1  is C 1  -C 6  alkyl, C 1  -C 6  haloakyl, --CH 2  CR 2  ═CR 3  R 4  or --CH 2  C.tbd.CR 5  ; 
     R 2  is hydrogen, halogen or methyl; 
     R 3  is hydrogen, halogen or methyl; 
     R 4  is hydrogen, halogen or methyl; and 
     R 5  is hydrogen, methyl or ethyl, 
     are prepared by reacting a nitrile of the formula II 
     
         R.sub.6 --CN                                               (II) 
    
     in which R 6  is C 1  -C 4  alkyl, phenyl or benzyl, is reacted with an alcohol of the formula III 
     
         R.sub.7 --OH                                               (III) 
    
     in which R 7  is C 1  -C 5  alkyl, benzyl or C 1  -C 4  alkoxyethyl, in an organic solvent which is only sparingly miscible with water or not at all, in the presence of hydrogen halide HX, the suspension obtained of the iminoester hydrohalide of the formula IV ##STR1## in which R 6  and R 7  are as defined above and X is chlorine, bromine or iodine, is added at a controlled rate to an aqueous suspension of a carbonate or hydrogen carbonate at a temperature of from -3° to +5° C., an aqueous solution of a hydroxylamine salt is added to the mixture obtained at a temperature of from -20° to -5° C., the aqueous phase is separated off after the mixture has been warmed to room temperature, the solution obtained of the hydroximic acid ester of the formula V ##STR2## in which R 6  and R 7  are as defined above, in an organic solvent is first treated with an aqueous solution of a strong base and then with an alkylating agent of the formula VI 
     
         Y--R.sub.1                                                 (VI) 
    
     in which R 1  is as defined above and Y is chlorine, bromine, iodine or --O--SO 2  R 8 , and R 8  is C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, phenyl or phenyl-substituted C 1  -C 4  alkyl, it being possible for the phenyl ring itself to be monosubstituted, disubstituted or trisubstituted by halogen or C 1  -C 4  alkyl, and Y is alternatively--OSO 2  OR 1  if R 1  is C 1  -C 2  alkyl, at from room temperature to the boiling point of the reaction mixture, the mixture is cooled to room temperature when the O-alkylation is complete, the aqueous phase is separated off, the oxime ether of the formula VII ##STR3## in which R 1 , R 6  and R 7  are as defined above, formed is hydrolysed by stirring with an aqueous solution of a strong acid, and the aqueous phase containing the salt of the O-substituted hydroxylamine of the formula I is separated off, and the hydroxylamine of the formula I is isolated, if necessary, by evaporating the water.

The present invention relates to a process for the preparation ofO-substituted hydroxylamines of the formula I

    H.sub.2 NOR.sub.1                                          (I)

in which

R₁ is C₁ -C₆ alkyl, C₁ -C₆ haloalkyl, --CH₂ CR₂ ═CR₃ R₄ or --CH₂C.tbd.CR₅ ;

R₂ is hydrogen, halogen or methyl;

R₃ is hydrogen, halogen or methyl;

R₄ is hydrogen, halogen or methyl; and

R₅ is hydrogen, methyl or ethyl,

and intermediates produced at some stage in this process.

The O-substituted hydroxylamines of the formula I are valuableintermediates in the preparation of herbicidally activeacylcyclohexanediones, as disclosed, for example, in European PatentApplication No. 0,243,313.

Preparation processes for O-substituted hydroxylamines and theirprecursors are described in the literature.

U.S. Pat. No. 4,743,701 discloses to prepare hydroximic acid esters ofthe formula ##STR4## in which R₉ and R₁₀, independently of one another,are alkyl, cycloalkyl, aryl or aralkyl, by reacting, in a first step, anitrile of the formula R₉ CN under anhydrous conditions with an alcoholof the formula R₁₀ -OH in an organic solvent in the presence of hydrogenhalide to give the corresponding imidate hydrohalide, separating off thesolid imidate hydrohalide from the reaction mixture and subsequentlyreacting this, in a second step, under anhydrous conditions in anorganic solvent with a hydroxylamine salt and with ammonia gas to givethe hydroximic acid ester of the formula VIII.

German Offenlegungsschrift No. 2,651,083 discloses to prepareO-substituted hydroxylamines of the formula IX ##STR5## in which R₁₂ isan ether, thiol, phenol or thiophenol radical or an amino group, byreacting a hydroximic acid ester of the formula X ##STR6## in which R₁₁is an alkyl or aryl radical, with a 2-propanol of the formula XI##STR7## in which Z is halogen or a sulfonate group, in a non-aqueousmedium in the presence of a base to give the O-substituted hydroximicacid esters of the formula XII ##STR8## and subsequently removing theprotecting group hydrolytically.

However, these known processes have a number of disadvantages. Thus, forexample, gaseous ammonia must be used for the preparation of thehydroximic acid esters of the formula VIII in accordance with U.S. Pat.No. 4,743,701, due to which large amounts of undesired ammonium saltsare produced as a byproduct. Besides the economically disadvantageousway in which the reaction is carried out in several steps, the anhydrousprocedure in the 2nd process step means that large amounts of organicsolvents are produced, whose recycling or disposal means additionalcosts.

The O-substituted hydroximic acid esters of the formula XII disclosed inGerman Offenlegungsschrift No. 2,651,083 likewise require anecologically unfavourable anhydrous procedure for their preparation. Thehydroximic acid esters of the formula X required as starting materialsfor this process must previously be prepared in a separate process.

It has now been found that the O-substituted hydroxylamines of theformula I can be prepared in good yield and purity in an economicallyand ecologically particularly advantageous manner when a nitrile of theformula II

    R.sub.6 --CN                                               (II)

in which R₆ is C₁ -C₄ alkyl, phenyl or benzyl, is reacted with analcohol of the formula III

    R.sub.7 --OH                                               (III)

in which R₇ is C₁ -C₅ alkyl, benzyl or C₁ -C₄ alkoxyethyl, in an organicsolvent which is only sparingly miscible with water or not at all, inthe presence of hydrogen halide HX, the suspension obtained of theiminoester hydrohalide of the formula IV ##STR9## in which R₆ and R₇ areas defined above and X is chlorine, bromine or iodine, is added at acontrolled rate to an aqueous suspension of a carbonate or hydrogencarbonate at a temperature of from -3° to +5° C., an aqueous solution ofa hydroxylamine salt is added to the mixture obtained at a temperatureof from -20° to -5° C., the aqueous phase is separated off after themixture has been warmed to room temperature, the solution obtained ofthe hydroximic acid ester of the formula V ##STR10## in which R₆ and R₇are as defined above, in an organic solvent is first treated with anaqueous solution of a strong base and then with an alkylating agent ofthe formula VI

    Y--R.sub.1                                                 (VI)

in which R₁ is as defined above and Y is chlorine, bromine, iodine or--O--SO₂ R₈, and R₈ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, phenyl orphenyl-substituted C₁ -C₄ alkyl, it being possible for the phenyl ringitself to be monosubstituted, trisubstituted by halogen or C₁ -C₄ alkyl,and Y is alternatively --OSO₂ OR₁ if R₁ is C₁ -C₂ alkyl, at from roomtemperature to the boiling point of the reaction mixture, the mixture iscooled to room temperature when the O-alkylation is complete, theaqueous phase is separated off, the oxime ether of the formula VII##STR11## in which R₁, R₆ and R₇ are as defined above, formed ishydrolysed by stirring with an aqueous solution of a strong acid, andthe aqueous phase containing the salt of the O-substituted hydroxylamineof the formula I is separated off, and the hydroxylamine of the formulaI is isolated, if necessary, by evaporating the water.

The alkyl groups occurring in the substituents may be straight-chain orbranched and are, for example, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl or the isomericpentyl radicals, n-hexyl or the isomeric hexyl radicals. Alkyl radicalshaving a maximum of 4 carbon atoms, in particular methyl and ethyl, arepreferred.

The phenyl and benzyl groups occurring in the substituent R₆ may beunsubstituted or substituted by halogen, nitro, C₁ -C₄ alkyl or C₁ -C₄haloalkyl, for example 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2,4-dichlorophenyl, 4-fluorophenyl, 4-methylphenyl, 2,4-dimethylphenyl,4-methylbenzyl, 4-nitrobenzyl, 4-trifluoromethylphenyl or 4-bromobenzyl.

Alkoxy is to be understood as meaning: methoxy, ethoxy, n-propxy,iso-propoxy or the four isomeric butoxy radicals, but in particularmethoxy or ethoxy.

Halogen, itself or as part of a substituent such as haloalkyl, isfluorine, chlorine, bromine and iodine, preferably chlorine and bromine.Haloalkyl is generally chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 2-chloroethyl, 2,2,2-trifluoroethyl,1,1,2,2-tetrafluoroethyl, pentafluoroethyl,1,1,2-trifluoro-2-chloroethyl, 2,2,2-trifluoro-1,1-dichloroethyl,pentachloroethyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl,2-chloroethyl and 3-chloropropyl, but in particular fluoromethyl,chloromethyl, difluoromethyl and trifluoromethyl.

Examples of phenyl-substituted C₁ -C₄ alkyl groups are 4-phenylbutyl,2-phenylethyl or benzyl. Examples of phenyl groups which are substitutedby halogen or C₁ -C₄ alkyl are 4-bromophenyl, 2,4-dichlorophenyl,2,4,6-trichlorophenyl, 4-fluorophenyl, 4-methylphenyl,2,4-dimethylphenyl, 4-ethylphenyl or 4-iso-propylphenyl. Preferredphenyl groups substituted by the abovementioned radicals are4-bromophenyl and 4-methylphenyl.

Organic solvents which are only sparingly (up to 10% by weight) misciblewith water or not at all and which are suitable for the processaccording to the invention are toluene, hexane, diethyl ether, xylene,cyclohexane, nitrobenzene, dichloroethane, dichloromethane ortrichloromethane. A very particularly preferred solvent is toluene.

Carbonates or hydrogen carbonates employed in the process according tothe invention for reaction with the iminoester hydrohalide of theformula IV are taken to mean, in particular, the alkali metal compounds,such as sodium carbonate, potassium carbonate, sodium hydrogen carbonateor potassium hydrogen carbonate. Sodium hydrogen carbonate is the mostpreferred.

The starting materials of the formulae II and III and the intermediatesof the formulae IV, V and VI of the process according to the inventionare known and in some cases commercially available.

The intermediates of the formula VII produced during the processaccording to the invention are novel, with the exception of thosecompounds in which R₁ is C₁ -C₆ alkyl, C₁ -C₆ haloalkyl or allyl, andlikewise form a subject-matter of the present invention. If desired, thecompounds of the formula VII can be isolated from the reaction mediumfor characterization purposes. If desired, the end products of theformula I can be obtained in free form by known methods by treatmentwith a base.

The reaction of the nitrile of the formula II with the alcohol of theformula III to give the iminoester hydrohalide of the formula IV isgenerally carried out at temperatures of from -10°to +30° C., preferably0°to 25° C. The preferred hydrogen halide HX here is hydrogen chloride.Before further reaction, the imidate hydrohalide reaction mixture can ifdesired be freed from unreacted hydrogen chloride by evacuation or bypassing in nitrogen.

Examples of hydroxylamine salts which are suitable for the processaccording to the invention are hydroxylamine hydrochloride,hydroxylamine sulfate and hydroxylamine phosphate, with hydroxylaminehydrochloride and hydroxylamine sulfate being the most preferred.

The alkylation of the hydroximic acid ester of the formula V is carriedout at temperatures of from room temperature to the boiling point of thereaction mixture. A preferred temperature range is between +50° and 80°C. Suitable strong bases for this process step are aqueous carbonatesand hydroxides of alkali metals and alkaline earth metals. Preferredstrong bases are aqueous sodium hydroxide and aqueous sodium carbonate.The hydroximic acid ester of the formula V, the alkylating agent of theformula VI and the base are preferably employed in equimolar amounts.

The alkylation is advantageously carried out in the presence ofcatalytic amounts of a phase-transfer catalyst. The phase-transfercatalyst is advantageously employed in an amount of from 0.01 to 10 mol%, preferably 0.5 to 1 mol %, based on the compound of the formula V.

Suitable phase-transfer catalysts are, in general, quaternary ammoniumsalts and crown ethers. Preferred phase-transfer catalysts are18-crown-6, benzyltrimethylammonium chloride, tetrabutylammoniumchloride, tetramethylammonium sulfate, tetramethylammonium chloride andtetrabutylammonium bromide. Tetrabutylammonium bromide is the mostpreferred.

The alkylation can be carried out particularly advantageously by using,as alkylating agent, a compound of the formula VI in which Y ischlorine, bromine, iodine, 4-methylphenylsulfonyl, 4-bromophenylsulfonylor methylsulfonyl, but in particular chlorine, bromine or iodine.

Particularly advantageous compounds of the formula I in which R₁ is--CH₂ CR₂ ═CR₃ R₄, where R₂, R₃ and R₄, independently of one another,are preferably hydrogen, chlorine, bromine or methyl, are prepared bythe process according to the invention.

Examples of strong acids which are suitable for the hydrolsis aremineral acids, such as hydrochloric acid, sulfuric acid or phosphoricacid; or sulfonic acids, such as methanesulfonic acid, benzenesulfonicacid or p-toluenesulfonic acid. Hydrochloric acid is the most preferred.

In the most preferred variant of the process according to the invention,acetonitrile and ethanol are reacted in toluene in the presence ofhydrogen chloride, the suspension obtained is added at a controlled rateto an ice-cooled, aqueous suspension of sodium hydrogen carbonate, anaqueous solution of hydroxylamine sulfate is added to the mixtureobtained at a temperature of from -20° to -5° C., the aqueous phase isseparated off after the mixture has been warmed to room temperature, thesolution obtained of ethyl acetohydroximate in toluene is treated firstwith an aqueous solution of sodium hydroxide and then withtrans-1,3-dichloropropene at a temperature of from +50° to +80° C., themixture is cooled to room temperature when the O-alkylation is complete,the aqueous phase is separated off, the ethylO-(trans-chloroally)acetohydroximate formed is hydrolysed by stirringwith dilute hydrochloric acid, and the aqueous phase containing thehydrochloride of O-(trans-chloroallyl)hydroxylamine is separated off andthe latter is isolated, if necessary, by evaporating the water.

Using the process according to the invention, the compounds of theformula I can be prepared at low cost from readily accessible startingmaterials in good yields and high purity. Compared with the processdisclosed in U.S. Pat. No. 4,743,701, only half the amount of undesiredammonium salts are produced as a byproduct by using sodium hydrogencarbonate as base.

It should furthermore be particularly advantageously emphasized that theprocess according to the invention is carried out without a solventchange and without isolating intermediates. This considerably reducesthe amount of time and apparatus complexity compared with knownprocesses.

The examples below serve to explain the process according to theinvention in greater detail.

EXAMPLE 1 Preparation of ethyl acetohydroximate ##STR12##

102 g of hydrogen chloride is passed over the course of two hours into amixture of 116.6 g of acetonitrile and 125.6 g of absolute ethanol in270 g of toluene at a temperature of from +12° to +15° C. The reactionmixture is subsequently stirred for 22 hours at a temperature of from+20° to +25° C. After the mixture has been cooled to -10° C., 234.4 g ofsodium hydrogen carbonate are added. A solution of 207.6 g ofhydroxylamine sulfate in 630 ml of water is subsequently added dropwiseover the course of one hour at a temperature of from --10° to --5° C.,CO₂ evolution occurring. The reaction mixture is subsequently stirredfor 90 minutes, warming slowly to room temperature. After the aqueousphase has been separated off, the organic phase is extracted with 200 mlof water. Separating off the aqueous phase gives a solution of 240.2 gof ethyl acetohydroximate (93.9% of theory) in toluene.

EXAMPLE 2 Preparation of O-(trans-chloroallyl)hydroxylaminehydrochloride (compound No. 1.1) ##STR13##

A solution, obtained as in Example 1, of 277.6 g of ethylacetohydroximate in toluene (content: 39%) is added dropwise over thecourse of 25 minutes to a solution of 173 g of 30% sodium hydroxidesolution in 173 ml of water. 3.2 g of tetrabutylammonium bromide aresubsequently added to the suspension produced. 115.7 g oftrans-1,3-dichloropropene (content: 96%) are added dropwise to thisreaction mixture over the course of 30 minutes at a temperature of from+60° to +65° C. After the mixture has been warmed to a temperaturebetween +70° and +75° C. for a period of 3 hours, the reaction mixtureis cooled to room temperature and the aqueous phase is subsequentlyseparated The organic phase, which contains the ethylO-(trans-chloroallyl)acetohydroximate (compound No. 2.1), is extractedtwice with 250 ml of water. The organic phase is subsequently addeddropwise over the course of 21/2 hours at a temperature of from +20° to+30° C. to a solution of 102.4 g of 32% hydrochloric acid in 54 ml ofwater. The reaction mixture is subsequently warmed at a temperature offrom +40° to 45° C. for a period of 21/2 hours and cooled to roomtemperature, and the aqueous phase is separated off. 270.3 g (87.5% oftheory, based on trans-1,3-dichloropropene) ofO-(trans-chloroallyl)hydroxylamine (compound No. 1.1) in the form of itshydrochloride (content: 46.6%) are obtained in aqueous solution.

228 g of the aqueous phase are evaporated at a pressure of 400 to 500 Paand a temperature of +60° C. After the residue has been dried in vacuoat +50° C., 108 g of O-(trans-choroallyl)hydroxylamine (compound No.1.1) in the form of its hydrochloride with a content of 98.5% and amelting point of from +164° to +165° C. are obtained. Afterrecrystallization from ethanol/diethyl ether, the melting point is +182°to +183° C.

The compounds listed in Tables 1 and 2 are prepared in correspondingmanner to the procedures described above:

                  TABLE 1                                                         ______________________________________                                        H.sub.2 NOR.sub.1.HCl          (I)                                            Compound No.                                                                            R.sub.1          M.p. [°C.]                                  ______________________________________                                        1.1                                                                                      ##STR14##       +182 to +183                                       1.2                                                                                      ##STR15##       +175 to +176                                       1.3                                                                                      ##STR16##       +165                                               1.4                                                                                      ##STR17##                                                          1.5                                                                                      ##STR18##                                                          1.6                                                                                      ##STR19##       +158 to +160                                       1.7       CH.sub.2CBrCBrH  (cis/trans mixture)                                1.8       CH.sub.2CHCCH.sub.3 Cl                                                                         (cis/trans mixture)                                1.9       CH.sub.2CCH      +152 to +153                                       1.10      CH.sub.3         +147 to +148                                       1.11      CH.sub.2 CH.sub.2 Cl                                                                           +180 to +181                                       ______________________________________                                    

                                      TABLE 2                                     __________________________________________________________________________     ##STR20##                         (VII)                                      Compound                       B.p. [°C.]/                             No.   R.sub.7  R.sub.6                                                                           R.sub.1     Pressure [Pa]                                  __________________________________________________________________________    2.1   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           ##STR21##  49-50°/200                              2.2   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           ##STR22##  68-69°/800                              2.3   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           ##STR23##  78°/5000                                2.4   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           ##STR24##  79°/2200                                2.5   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           ##STR25##  77°/1100                                2.6   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           ##STR26##  60-61°/1000                             2.7   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          CH.sub.2 CBrCBrH                                                                          89-90°/40                                                              (cis/trans                                                                    mixture)                                       2.8   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          CH.sub.2CHCCH.sub.3 Cl                                                                    93°/1500                                                               (cis/trans                                                                    mixture)                                       2.9   C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          CH.sub.2CCH 40°/500                                 2.10  C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                    ##STR27##                                                 2.11  C.sub.2 H.sub.5                                                                        i-C.sub.3 H.sub.8                                                                  ##STR28##                                                 2.12  C.sub.2 H.sub.5                                                                        Phenyl                                                                             ##STR29##                                                 2.13  C.sub.2 H.sub.5                                                                        Benzyl                                                                             ##STR30##                                                 2.14  CH.sub.3 CH.sub.3                                                                           ##STR31##                                                 2.15  i-C.sub.3 H.sub.8                                                                      CH.sub.3                                                                           ##STR32##                                                 2.16  Benzyl   CH.sub.3                                                                          CH.sub.2 CBrCBrH                                           2.17  C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          CH.sub.3    +106 to +107                                   2.18  C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          CH.sub.2 CH.sub.2 Cl                                                                      +41/250                                        2.19  CH.sub.3 OCH.sub.2 CH.sub.2                                                            CH.sub.3                                                                          CH.sub.2CCH                                                __________________________________________________________________________

What is claimed is:
 1. A compound of the formula VII ##STR33## in whichR₇ is C₁ -C₅ alkyl, benzyl or C₁ -C₄ alkoxyethyl;R₆ is C₁ -C₄ alkyl,phenyl or benzyl; R₁ is -CH₂ CR₂ ═CR₃ R₄ or -CH₂ C.tbd.CR₅ ; R₂ ishydrogen, halogen or methyl; R₃ is hydrogen, halogen or methyl; R₄ ishydrogen, halogen or methyl and R₅ is hydrogen, methyl or ethyl, withthe proviso that R₂, R₃ and R₄ are not simultaneously hydrogen.
 2. Acompound of the formula VII according to claim 1, wherein R₇ and R₆,independently of one another, are C₁ -C₂ alkyl.
 3. A compound of theformula VII according to claim 1, wherein R₁ is --CH₂ CR₂ ═CR₃ R₄.
 4. Acompound of the formula VII according to claim 1, wherein R₂, R₃ and R₄,independently of one another, are hydrogen, chlorine, bromine or methyl.5. A compound of the formula VII according to claim 1, wherein R₁ ischloroallyl.
 6. Ethyl O-(trans-chloroallyl)acetohydroximate according toclaim 1.